ArticleYeast (Chichester, England)2010
Chemical inhibition of CaaX protease activity disrupts yeast Ras localization.
Article in Yeast (Chichester, England), 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Targeting MDM2, RAS, and PCNA for cancer targeted therapy: pan-cancer approaches vs. cancer-specific strategies.Frontiers in pharmacology · 2025Review
- To each its own: Mechanisms of cross-talk between GPI biosynthesis and cAMP-PKA signaling in Candida albicans versus Saccharomyces cerevisiae.The Journal of biological chemistry · 2024Review
- Targeted genetic and small molecule disruption of N-Ras CaaX cleavage alters its localization and oncogenic potential.Bioorganic chemistry · 2024Article
- Specific Disruption of Ras2 CAAX Proteolysis Alters Its Localization and Function.Microbiology spectrum · 2023Article
- Post-embryonic endogenous expression and localization of LET-60/Ras inmicroPublication biology · 2023Article
- Defective synaptic plasticity in a model of Coffin-Lowry syndrome is rescued by simultaneously targeting PKA and MAPK pathways.Learning & memory (Cold Spring Harbor, N.Y.) · 2022Article
- Post-translational modification of KRAS: potential targets for cancer therapy.Acta pharmacologica Sinica · 2021Review
- Concepts and advances in cancer therapeutic vulnerabilities in RAS membrane targeting.Seminars in cancer biology · 2019Review
- Inhibition of Ras activity coordinates cell fusion with cell-cell contact during yeast mating.The Journal of cell biology · 2018Article
- Rce1: mechanism and inhibition.Critical reviews in biochemistry and molecular biology · 2018Review
- C-terminus Proteolysis and Palmitoylation Cooperate for Optimal Plasma Membrane Localization of RasA inFrontiers in microbiology · 2018Article
- A shunt pathway limits the CaaX processing of Hsp40 Ydj1p and regulates Ydj1p-dependent phenotypes.eLife · 2016Article
- 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells.Bioorganic & medicinal chemistry · 2016Article
- Allosteric regulation of rhomboid intramembrane proteolysis.The EMBO journal · 2014Article
- Diazirine-containing photoactivatable isoprenoid: synthesis and application in studies with isoprenylcysteine carboxyl methyltransferase.The Journal of organic chemistry · 2014Article
- Targeting mutant KRAS for anticancer therapeutics: a review of novel small molecule modulators.Journal of medicinal chemistry · 2013Review
- Yeast glucose pathways converge on the transcriptional regulation of trehalose biosynthesis.BMC genomics · 2012Article
- Article
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Authors and funding
5 authors.
Funding
Abstract
Proteins possessing a C-terminal CaaX motif, such as the Ras GTPases, undergo extensive post-translational modification that includes attachment of an isoprenoid lipid, proteolytic processing and carboxylmethylation. Inhibition of the enzymes involved in these processes is considered a cancer-therapeutic strategy. We previously identified nine in vitro inhibitors of the yeast CaaX protease Rce1p in a chemical library screen (Manandhar et al., 2007). Here, we demonstrate that these agents disrupt the normal plasma membrane distribution of yeast GFP-Ras reporters in a manner that pharmacologically phenocopies effects observed upon genetic loss of CaaX protease function. Consistent with Rce1p being the in vivo target of the inhibitors, we observe that compound-induced delocalization is suppressed by increasing the gene dosage of RCE1. Moreover, we observe that Rce1p biochemical activity associated with inhibitor-treated cells is inversely correlated with compound dose. Genetic loss of CaaX proteolysis results in mistargeting of GFP-Ras2p to subcellular foci that are positive for the endoplasmic reticulum marker Sec63p. Pharmacological inhibition of CaaX protease activity also delocalizes GFP-Ras2p to foci, but these foci are not as strongly positive for Sec63p. Lastly, we demonstrate that heterologously expressed human Rce1p can mediate proper targeting of yeast Ras and that its activity can also be perturbed by some of the above inhibitors. Together, these results indicate that disrupting the proteolytic modification of Ras GTPases impacts their in vivo trafficking.
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